Oxazolidinones represent a novel chemical class of synthetic antimicrobial agents. Following a chequered historical development since about the early-1980s, a watershed event took place with the clinical development and release for medical use in the late 2000s of the first compound, Linezolid, of this class (Slee A M, et al., Antimicrob. Agents Chemother (1987) 31:1791-1797; 2nd European Congress of Chemotherapy and 7th Biennial Conference on Antiinfective Agents and Chemotherapy (Final Program), (1998): 93).
This advance enabled the profiling of the unique properties of the members of this class, which is that they display activity against important Gram-positive human and veterinary pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE) and β-lactam resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria and Gram-positive and Gram-negative anaerobes. (Diekema D J et al., Lancet 2001; 358: 1975-82).
Deficiencies of this class of oxazolidinones have also surfaced. They are inactive against Enterobacteriaceae (Zhanel, G G et al., Canadian Journal of Infectious Diseases, 2001, 12:379-390). Moreover their potency for atypical respiratory pathogens such as Mycoplasma pneumoniae, M. hominis, Ureaplasma urealyticium and Chlamydia species is of a borderline range which could result in unacceptable clinical efficacy for the treatment of respiratory tract infections (Diekema D. J. et al. Lancet 2001; 358:1975-82).
Other limitations that have appeared through the clinical development studies and use of Linezolid and its potential successors in development are that the class has a propensity to induce myelosuppression with consequent thrombocytopenia (Kuter D J et al., Pharmacotherapy, 2001: 21: 1010-1030).
Inhibition of monoamine oxidase by oxazolidinones has prompted a recommendation made to clinicians that clinical use of members of this class be done with caution during concomitant usage of adrenergic or serotonergic agents and selective serotonin reuptake inhibitors (Ament P W et al., Am Fam Physician 2002, 65: 663-70).
Linezolid is shown to have two targets in cells for its inhibitory effects. It binds to the 50S subunit within domain V of the 23S or RNA peptidyl transferase center near the interface with the 30S subunit, thereby blocking the formation of the tMet-tRNA-ribosome-mRNA ternary complex. In addition, linezolid associates with the nascent 50S particle and stops the assembly process (Shinabarger D, Exp. Opin. Invest. Drugs (1999) 8:1195-1202; Champrey W S et al., Curr. Microb. 2002, 44: 350-356).
There are several patents which refer to oxazolidinones having antibacterial activity.
WO95/25106 dated Sep. 21, 1995 discloses substituted piperidino phenyloxazolidinones. This corresponds to U.S. Pat. No. 5,668,286 and EP 0 750 618.
WO96/13502 dated May 9, 1996 discloses phenyloxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety.
Our pending US Patent Publication No. US 2004-0063954 and PCT application Nos. WO2004/007489 and WO 2004/007488 disclose piperidinyl phenyl oxazolidinones for antimicrobial use.
Pyrrodinyl/piperidinyl phenyl oxazolidinone antibacterial agents are also described in Kim H Y et al., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230.
The following citations pertain to oxazolidinones some of which have spirocyclic oxazolidinone derivatives where one of the hetero atoms in the ring is nitrogen.
1) WO 96/35691 dated Nov. 14, 1996 discloses spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinone derivatives where one of the hetero atoms in the ring is nitrogen. This corresponds to U.S. Pat. No. 6,090,820 and EP 0828,741 B1.
2) WO 02/080841 A2 dated Oct. 17, 2002,
3) WO 02/081470 A1 dated Apr. 7, 2001,
4) WO 02/081469 A1 dated Oct. 17, 2002 and
5) WO 02/081468 A1 dated Oct. 17, 2002, WO 01/81350 A1 dated Nov. 1, 2001.
Other publications are as follows:
WO 99/24428 dated May 20, 1999 discloses diazepeno phenyloxazolidinone derivatives.
WO 02/06278 dated Jan. 24, 2002 discloses substituted aminopiperidino phenyloxazolidinone derivatives.
Our pending US Application No. US 2004-0063954 and PCT application Nos. WO 2004/007488 and WO 2004/007489 and Indian application No. 915/MUM/2003 disclose a novel series of oxazolidinones which display increased potency, and incorporate bactericidal activity, in contrast to the earlier-described bacteriostatic activity of Linezolid and literature described oxazolidinones. Unusual bactericidal activity is shown to be displayed not just against Linezolid-sensitive strains but also for the first time against Linezolid-resistant strains, thus indicating a differential binding at conventional site/s of the ribonucleoprotein and/or targeting multiple such receptor sites.
The present inventors have found that the novel antibacterially efficacious piperidino substituted phenyloxazolidinones of the invention herein described have a favourable in vivo efficacy and pharmacokinetic profile and safety advantages.
The compounds of the present invention are novel, none of them having being previously reported in the literature. They are non-obvious over the compounds in the prior art by virtue of their being in vivo efficacious. While not being bound by any theory, it is surmised by displaying in vivo efficacy, the compounds of the invention thus establish their ability to give in vivo protection to animals and be useful clinically.